1. Good Manufacturing Practices for Blood Establishments
(GMP for plasma donations)
Dr A Padilla
Blood Products & related Biologicals
Quality Assurance and Safety: Medicines
World Health Organization

2. OUTLINE OUTLINE The GMP concept Good Manufacturing Practices for BE
GMP compliance
Impact of QA/GMP approach
Website references

3. GMP IN BLOOD ESTABLISHMENTS
GMP* addresses the manufacturing activities (collection, testing, process, storage, labelling, distribution) of the blood establishment
Implementation of GMP requires to separate medical functions from manufacturing activities (e.g. plasma) in blood establishments
*GMP applies to products and processes

4. WHA63.12: "Blood Products" definition
"Any therapeutic substances derived from human blood, including whole blood, labile blood components and plasma-derived medicinal products"

5. WHAT DO WE NEED TO ACHIEVE THROUGH GMP?
CONTROL INHERENT BIOLOGICAL VARIABILITY*
CONSISTENCY OF PRODUCTION/PROCESSES
TRACEABILITY DONOR RECIPIENT
* each individual donation is unique

6. HOW TO MANAGE THIS?
To control the high variability, we need proof of a robust collection and production process
To control the process, we need a systematic approach (the QA/GMP approach) to ensure compliance at all steps involved
To apply the systematic production approach, each intermediate and final product must fulfil defined quality requirements: pre-defined validated specifications

7. GMP: A TOOL TO CONTROL PROCESS VARIABILITY*
important to understand which characteristics are most relevant, and their impact, on products and processes
measurable characteristics
trend analysis to observe processes
effective change control mechanisms
* human plasma has intrinsic biological variability

8. TRACEABILITY FROM DONOR TO PATIENT
World Health Organization
TRACEABILITY FROM DONOR TO PATIENT
19 April 2017
Blood
donation
Plasma for
Fractionation
Components
Plasma-Derived
Medicinal Product
Patients
FRACTIONATION
VIRAL INACTIVATION
DONOR
INFORMATION
COMPONENTS SEPARATION
TREATMENT
The GMP concept: GMP applies to products and processes. It is a tool to determine consistency of the production process versus pre-defiend spevifications. The donor is the raw material and the plasma is separated from whole blood donation is used for transfuion and as red cells needs are higher there is plasma left behind which if possible we want to use fro frcationation
Good Manufacturing Practices

9. TRACEABILITY FROM DONOR TO PATIENT
Blood/Plasma
donation
Blood
Components
Patients
Plasma for
Fractionation
Plasma-Derived
Medicinal Product
COMPONENTS PREPARATION, e.g.
production process
testing
process control
release
storage & transport
DONOR/DONATION
donor population
donor registration
donor selection
donor protection
collection process
FRACTIONATION, e.g.
fractionation process
viral inactivation
QC & release
distribution

10. TRACEABILITY IS KEY unique donor/donation number
clear identification of donor, donation, products
post donation information
effective information system between blood establishment, testing lab, hospital or plasma supplier and fractionation plant
must work in both ways donor-patient-donor

11. Quality Assurance Program
Plasma Contract Fractionation Programs - Need for GMP implementation in BE -
GMP- common principles
PLASMA
SUPPLIER
FRACTIONATOR
Nat.Reg.
Authority
Licensing
GMP
Quality Assurance Program
GMP
Licensing
Plasma Contract
fractionation
across countries

12. FROM DONOR TO PATIENT TRACEABILITY LOOK BACK SYSTEM Blood/Plasma
donation
Plasma for
Fractionation
Blood
Components
Plasma-Derived
Medicinal Product
Patients
FRACTIONATION
VIRAL INACTIVATION
COLLECTION
PROCESS
COMPONENTS PREPARATION
TREATMENT
TRACEABILITY
LOOK BACK SYSTEM

13. Good Manufacturing Practices (GMP) for Blood establishments (BE): Definition
GMP is that part of QUALITY ASSURANCE that ensures that products are consistently produced to the quality standards appropriate to their intended use, as required by predefined specifications and, if applicable, by the marketing authorisation.
GMP is concerned with both production and quality control.
WHO Guidelines for Blood Establishments (TRS 961, Annex 4):

14. World Health Organization
19 April 2017
GMP compliance: issues specific to the production of blood components, including plasma for fractionation

15. WHO GMP Guidelines contain...
.. general GMP topics, e.g. quality management
.. specific topics to manufacturing of blood components, from donor selection through distribution of final product
.. newer GMP concepts, e.g. risk management, product quality reviews

16. Structure of the Document
Chapters 1 – 2: Introduction, Glossary/Abbrev.
Chapters 3 – 8: Quality Management
Chapter 9: Manufacturing
Chapters 10: Contract manufacturing, analysis and services
Chapters : Acknowledgements/References

17. Chapters 3 – 8 Quality Management Personnel Documentation
Principles, Product Quality Review, Quality risk management, Change control, Deviation evaluation and reporting, Corrective and preventive actions, Internal audits, Complaints and product recall, Process Improvement, Look back
Personnel
Organisation and responsibilities, Training, Personal hygiene
Documentation
SOP and records, Documentation control

18. Chapters 3 – 8 (cont.) Premises and Equipement
Premises, Equipment, Computerized-systems
Qualification and Validation
Qualification of equipment, Validation of manufacturing processes, selection of an appropriate test system, Assay performence validation
Management of Materials and Reagents
Materials and reagents, Receipt/Quarantine/Release/Storage/Traceability of material, Supplier/Vendor management

19. Chapter 9: Manufacturing
Process-specific guidance
Donor registration, Donor selection, Collection, Component preparation, Laboratory testing, Quality control, Labelling, Release, Dispatch, Shipping, Returns
Product characteristics
Whole blood, Red cells, Platelets, plasma for transfusion, plasma for fractionation, Cryoprecipitate/CPP
Points to consider for validation of production steps
Centrifugation, Separation, Freezing, Leukocyte reduction, Irradiation

20. GMP compliance....... the principle
The production process must
Be validated
Be reproducible
Be clearly specified and documented
Be in accordance with the licensed process (at all times)
Change must be managed
Planned change(s) should be controlled
Unplanned changes (deviations) should be
Recorded
Reviewed for impact on product Safety, Quality and Efficacy

21. GMP compliance…… plasma variability
A robust (standardized) process required
Knowledge of the production process competence needed:
Knowledge of the plasma characteristics
Knowledge of impact on processes and products
Process optimization for those characteristics
Process documentation: change control to manage modifications
Trend analysis to monitor the process (behaviour over time)

22. GMP compliance … the culture inside the organization
The culture of the organisation should encourage:
respect for the defined process
respect for the planned change mechanism
openness in timely reporting of deviations
commitment to determine variation cause
recognition of the benefits of trend analysis
determination to learn from past mistakes

23. World Health Organization
19 April 2017
SUMMARY
Suitability of plasma depends on meeting production standards for blood collection and component manufacturing
control of processes end-to-end required for production of all blood components

24. IMPACT OF GMP IN BLOOD ESTABLISHMENTS (I)
In blood establishments, GMP introduces the application of quality assurance principles in all steps involved in the collection, production and testing of blood components
GMP supports systematic application of donor selection criteria for each donation
GMP reduces errors and technical problems in collection, production, testing, and distribution

25. IMPACT OF GMP IN BLOOD ESTABLISHMENTS (III)
Implementation of GMP in blood establishments has shown to be a beneficial tool to help countries in improving plasma quality
GMP in blood establishments will increase availability of plasma and is one of the key issues for a successful plasma contract fractionation program and/or domestic fractionation

26. World Health Organization
19 April 2017
WHO guidance documents: website addressed
Reference on GMP for blood establishments (2011):
Reference on production, control and regulation of plasma for fractionation (2007):
Reference on viral inactivation and removal procedures (2005):
Catalogue of blood products and blood safety related reference materials:

27. http:// www.who.int/bloodproducts
Based on this experience, the core Key words that can be spread all governments, regulatory institutions as well as to all health professional , the public and the media is that without 1) a strong political commitment to develop and sustain an independent and competent national regulatory system and 2) a systematic institutional development plan to address gaps and new challenges
governments will face risk not to be able to reduce the public threat due to unsafe,ineffective, poor quality product or misleading/incomplete information.
As I mentioned earlier, we also have lessons learned and to day China and Tunisia are going to show us how they have developed independent and competent NRAs. Thank you Mr Chair.

28. World Health Organization
Web site addresses
19 April 2017